基于家系的Tim-3基因多态性与儿童变应性哮喘的关联研究

目的 以家系资料为基础,利用遗传不平衡原理探讨染色体5q33.2区Tim-3基因启动子两个多态性位点rs10053538和rs10515746与中国湖北地区汉族儿童变应性哮喘的关系.方法 应用限制性片段长度多态性技术结合测序方法,分析了118个儿童变应性哮喘核心家系Tim-3基因rs10053538和rs10515746的基因型;采用基于家系的关联分析方法,包括单体型相对风险分析(HRR)和传递不平衡检验(TDT),分析基因分型数据;应用Transmit软件构建单体型并进行单体型关联分析.结果 118个核心家庭HRR分析显示Tim-3基因启动子区两个多态性位点rs10053538和rs10515746不使病人具有更高的发病风险(X2=2.430,P>0.05;x2=1.368,P>0.05).118个满足经典TDT分析的核心家庭中,杂合子父母传递给患病子代的等位基因频率不比预期值高(x2=2.042,P>O.05;x2=0.750,P>O.05).Transmit双位点单体型分析也未见父母传递给子女各个单体型的观察值和期望值有明显差异(P>O.05).结论 中国湖北地区汉族人群中,Tim-3基因启动子区两个多态性位点rs10053538和rs10515746与儿童变应性哮喘不具有相关性.     

基于家系的Tim-1基因启动子多态性与儿童过敏性哮喘的关联研究

目的:以家系资料为基础,利用遗传不平衡原理探讨染色体5q31-33区Tim-1基因启动子3多态性-2562GA、-416CG和-232GA与湖北地区汉族儿童过敏性哮喘的关系。方法:应用限制性片段长度多态性技术分析了118个儿童过敏性哮喘核心家系Tim-1基因-2562GA、-416CG和-232GA多态性位点的基因型;采用基于家系的传递不平衡检验(TDT)分析基因分型数据;应用TRANSMIT软件构建单倍型并进行单体型关联分析。结果:①118个核心家庭TDT分析显示-2562GA、-232GA位点由杂合子父母传递给患病子代的等位基因频率没有偏离50%,差异无显著性(P0.05),-416CG位点由杂合子父母传递给患病子代的G等位位点的观察值明显高于期望值(P0.05)。②TRANSMIT单体型传递不平衡分析显示父母传递给患病子女GCA和GGA单体型的观察值与期望值差异有显著性(P0.05);Globalχ2检验结果显示Tim-1的单体型与儿童过敏性哮喘有关联(χ2=17.26,P0.01)。结论:Tim-1基因启动子的-416CG位点与中国湖北地区汉族儿童过敏性哮喘易感性相关,由其构建的单体型也与哮喘相关。Tim-1基因遗传多态性可能在哮喘的发病中起重要的作用。     

中国汉族人群γ-氨基丁酸A类受体基因簇与孤独症的关联研究

目的:探讨染色体15q12区域γ-氨基丁酸A类受体基因簇的单核苷酸多态性与中国汉族孤独症人群的遗传关联。方法:选取502个中国汉族孤独症核心家系(包括502例患者及健康的生物学父母1004例),孤独症儿童符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)孤独症诊断标准。通过Agena Bioscience质谱检测平台,对γ-氨基丁酸A类受体基因簇中GABRB3、GABRA5和GABRG3基因的15个标签单核苷酸多态性位点进行基因分型。在孤独症核心家系中进行以家系为基础的关联检验,比较父母携带的杂合型等位基因传递给孤独症子代的概率。结果:位于GABRG3基因单核苷酸多态性位点rs7180500的等位基因C和位于GABRB3基因单核苷酸多态性位点rs4906902的等位基因A存在父母向孤独症子代的优先传递(Z=3.573,P0.001;Z=3.141,P=0.002);经Bonferroni校正后仍具有统计学意义。结论:在中国汉族人群中,位于染色体15q12区域的GABRG3和GABRB3基因可能是孤独症的易感基因。     

DIO2基因单核苷酸多态性与精神发育迟滞相关性研究

目的探讨DIO2基因多态性及单倍型与精神发育迟滞的相关关系。方法本研究以344个汉族精神发育迟滞患者及其亲属组成的家系为研究对象．在DIO2上选择了3个合适的SNPs作为标记．利用PCR—SSCP和PCR—RFLP方法完成基因分型。应用FBAT软件对多态位点及可能组成的单倍型与精神发育迟滞的关系进行分析。结果单个位点家系关联性分析结果提示：rs225015、rs225014和rs225012位点各等位基因从亲代传递给患病子代没有观察到显著性（P〉0．05）。多态性位点间的连锁不平衡检验显示：3个位点rs225015、rs225014和rs225012均具有较高的连锁不平衡（D’〉0．8）。单倍型分析结果显示：3个位点构成的单体型GTG在附加遗传模型（Z=2．226,P=0．026019）和隐性遗传模型（Z=2．651,P=0．008023）与MR相关。结论DIO2基因可能与精神发育迟滞的易感性有关。     

湖北汉族人群Tim-3基因启动子及编码区的分子突变

目的：检测湖北汉族人群Tim-3基因启动子区和编码区的单核苷酸多态性，寻找Tim-3基因的遗传标记。方法：采用分段扩增直接测序的方法检测60名湖北汉族人Tim-3基因的启动子区、全部的外显子区及部分内含子区，将测序结果与NCBI及HapMap计划库中其他人种的数据进行对比，确定湖北汉族人群Tim-3基因突变的位置、类型和频率。结果：在Tim-3基因启动子区和外显子区共发现9个SNPs，包含5个已报道的SNPs和4个新发现的突变位点。湖北汉族人群中检出的4个SNPsrs4704853、rs10515746、rs4704846、rs9313439与Ft本人分布相似（P〉0．05），与欧洲人及非洲人的分布则有统计学意义（P〈0．01）。结论：湖北汉族人群Tim-3基因的SNPs分布有别于其他人种，可为在汉族人群中研究Tim-3基因与疾病关联提供依据。     

神经型烟碱乙酰胆碱受体α7亚单位基因多态性与精神分裂症的传递不平衡研究

目的 探讨神经型烟碱乙酰胆碱受体α7亚单位基因(neuronal nicotinic acetyleholine receptor α7 subunit gene,CHRNA7)多态性与精神分裂症的关系.方法 应用聚合酶链反应及聚丙烯酰胺凝胶芯片技术检测129个精神分裂症先证者核心家系CHRNA7基因的rs2337980、rs1909884、rs883473三个单核苷酸多态性,并采用基于单倍型的单倍型相对风险检验(haplotype relative risk,HHRR)、传递不平衡检验(transmission disequilibrium test,TDT)及单倍型分析进行统计.结果 (1)HHRR分析结果显示rs2337980位点精神分裂症患者组与虚拟对照组之间等位基因频率差异有统计学意义(P=0.017);(2)TDT分析发现,rs2337980位点与精神分裂症之间可能存在传递不平衡,杂合子父母过多的传递等位基因C给患病子女(P=0.021).(3)单倍型分析发现,rs2337980、rsl909884及rs2337980、rsl909884、rs883473组成的单倍型与精神分裂症有显著相关(总体P=0.034;glohal P=0.027),其中T-C,T-C-T两个单倍型与精神分裂症可能存在传递不平衡.结论 CHRNA7 基因多态性可能与精神分裂症存在关联,rs2337980的变异等位基因T可能是精神分裂症的保护性因子.     

特应症患者CCl6基因多态性分析

目的 研究CC16基因多态性与特应症遗传易感性之间的关系。方法 应用聚合酶链式反应(PCR)和限制性片段长度多态性(RFLP)方法，观察了42个特应症核心家系(n＝135)中CC16基因38A／G多态性的遗传分布情况,并用基于单体型的单体型相对风险关联(HHRR)和传递不平衡检验(TDT)进行关联和连锁分析。结果 HHRR关联分析显示等位基因38A与粉尘过敏，高sIgE显著关联(P分别     

TMX基因多态性与先天性肥厚性幽门狭窄易感性的传递不平衡检验分析

目的 探索TMX基因外显子6上的多态性位点rs7161242[ c.492T＞G]及外显子7上的多态性位点rs7160810[ c.648 G＞A]与先天性肥厚性幽门狭窄(CHPS)发病易感性的关联.方法 对广州市第一人民医院收治的22个汉族核心家系(CHPS患者及父母)采用PCR及测序的方法进行基因分型.应用传递不平衡检验(TDT)判断基因多态性与CHPS发病的关联.结果 测序结果未发现新的突变位点;患儿及父母组内这两个多态性位点的Hardy-Wcinberg平衡检验均P＞0.05.TDT检验提示多态性位点rs7161242的G等位基因及rs7160810的A等位基因均与CHPS发病相关,其p值分别为2.0×10-4和5.699x10-5.连锁不平衡分析结果提示,这两个位点的r2为0.757,D′值为0.893,成紧密连锁.结论 TMX基因的多态性位点rs7161242[ c.492T＞G]及rs7160810[c.648 G＞A]与中国汉族人群CHPS发病密切相关.     

TNFSF4基因多态性与汉族儿童变应性鼻炎和哮喘易感性相关

目的变应性鼻炎(allergic rhinitis,AR)和哮喘是呼吸道常见的慢性非传染性免疫性疾病,其联系密切,经常共存。关于TNFSF4基因的单核苷酸多态性(SNPs)的研显究示其与多种免疫性病相关。我们旨在探讨TNFSF4基因多态性是否在不伴AR的哮喘和伴有AR的哮喘儿童中拥有遗传易感性。方法设计病例对照研究,其中包括320名哮喘(伴与不伴AR)儿童与240名健康对照组。使用聚合酶链反应-限制性片段长度进行检测基因多态性(PCR-RFLP),总共包括TNFSF4基因6个位点(rs1234313,rs1234314,rs1234315,rs12039904,rs844648和rs10912580)。结果 TNFSF4中的3个SNP位点(rs1234313,rs1234314和rs1234315)与AR和哮喘显著相关。结论本研究认为TNFSF4中的SNPs与汉族儿童的AR和哮喘遗传易感性相关。     

G-蛋白信号转导调节子4(RGS4)基因多态性与精神分裂症的关联研究

目的：探讨G-蛋白信号转导调节子4（regulator of G-protein signaling-4，RGS4）基因与精神分裂症及临床症状的遗传关联。方法：应用病例对照关联研究设计，采用聚合酶链式反应-限制性片断长度多态性（PCR-RFLP）和DNA测序方法，分析386例精神分裂症患者和390例正常对照者中RGS4基因4个单核苷酸多态性（SNP）位点与精神分裂症的关联。并采用阳性和阴性症状量表（PANSS）评估患者的临床症状，进一步分析PANSS因子分与RGS4多态性的关联。结果：RGS4基因的两个多态性位点rs12753561（T〉G，χ^2=8．970，P=0．002）和rs10759（C〉A，χ^2=13．773，F=0．002，P=0．002）与精神分裂症关联，由上述4个SNPs组成的多个单体型如AAGA（χ^2=11．120，P=0．0008，OR=0．52，95％CI=0．36—0．77）和GGGC（χ^2=10．096，P=0．001，OR=1．43，95％CI=1．15—1．79）均与精神分裂症关联。PANSS量表的阴性症状因子分与rs12753561（t=2．216，P=0．029）和rs10759（t=2．543，P=0．012）关联。结论：RGS4基因多态性与精神分裂症及阴性和一般精神病理症状显著关联。     

Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.     

ADAM33 polymorphisms are associated with asthma susceptibility in a Japanese population

BACKGROUND: Asthma is the most common chronic disorder in childhood, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Asthma is believed to be a complex disorder involving genetic and environmental factors, and several asthma susceptibility loci have been identified through genome-wide screening. A disintegrin and metalloprotease 33 (ADAM33) was the first asthma susceptibility gene to be discovered by positional cloning in 2002. OBJECTIVE: The aim of the present study was to investigate whether single-nucleotide polymorphisms (SNPs) in ADAM33 are associated with childhood asthma in the Japanese population. METHODS: Twenty-three ADAM33 SNPs were genotyped by fluorescence correlation spectroscopy with the use of DNA from 155 families (538 members) identified through children with atopic asthma. The transmission disequilibrium test (TDT) was performed for family-based association study. RESULTS: TDT revealed that minor alleles of S+1, ST+4, and T2 SNPs were over-transmitted to asthma-affected offspring (P<0.05). According to the haplotype TDT, no haplotype of ADAM33 was transmitted preferentially to asthmatic offspring. CONCLUSION: Our results confirm the involvement of ADAM33 in the development of childhood asthma among the Japanese.     

Gene-based single nucleotide polymorphisms and linkage disequilibrium patterns of 29 asthma candidate genes in the chromosome 5q31-33 region in Koreans

BACKGROUND AND METHODS: Numerous genetic studies have mapped asthma susceptibility genes to a region on chromosome 5q31-33 in several populations. This region contains a cluster of cytokines and other immune-related genes important in immune response. In the present study, to determine the genetic variations and patterns of linkage disequilibrium (LD), we resequenced all the exons and promoter regions of the 29 asthma candidate genes in the chromosome 5q31-33 region. RESULTS: We identified a total of 314 genetic variants, including 289 single nucleotide polymorphisms (SNPs), 22 insertion/deletion polymorphisms and 3 microsatellites. Standardized variance data for allele frequency revealed substantial differences in SNP allele frequencies among different ethnic groups. Interestingly, significant ethnic differences were observed mainly in intron SNPs. LD block analysis using 174 common SNPs with a frequency of >10% disclosed strong LD within most candidate genes. No significant LD was observed across genes, except for one LD block (CD14-IK block). Gene-based haplotype analyses showed that 1-5 haplotype-tagging SNPs may be used to define the six or fewer common haplotypes with a frequency of >5%, regardless of the number of SNPs. CONCLUSION: Overall, our results provide useful information for the identification of immune-mediated disease genes in the chromosome 5q31-33 region, as well as valuable evidence for gene-based haplotype analysis in disease association studies.     

The transmission disequilibrium analysis between neuronal nicotinic acetylcholine receptor alpha 7 subunit gene polymorphisms and schizophrenia]

OBJECTIVE: To investigate the association between neuronal nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) gene and schizophrenia. METHODS: The three polymorphisms rs2337980, rs1909884, rs883473 in CHRNA7 gene were detected based on PCR and polyacrylamide gel microarray in 129 schizophrenic trios. The results of genotyping were analyzed by haplotype relative risk analysis based on haplotype(HHRR), transmission disequilibrium test(TDT) and hyplotype analysis. RESULTS: (1)The HHRR analysis suggested that there was significant differences in rs2337980 allele frequencies between schizophrenia group and dummy control group(P= 0.017); (2)In TDT test, there may be transmission disequilibrium between rs2337980 and schizophrenia, the heterozygous parents excessively transferred the C allele to patients (P= 0.021); (3)The haplotype between rs2337980 and rs1909884 as well as the hyplotype among rs2337980, rs1909884 and rs883473 may have significant association with schizophrenia (global P= 0.034; global P= 0.027), the T-C and T-C-T hyplotype may have transmission disequilibrium with schizophrenia. CONCLUSION: There may be association between CHRNA7 gene polymorphisms and schizophrenia, the variant allele T in rs2337980 may have a protective effect to schizophrenia.     

抑郁症与cAMP反应元件结合蛋白基因的关联研究

目的 探讨cAMP反应元件结合蛋白(cyclic adenosine monophosphate response elementbinding protein,CREB1)基因与抑郁症的关联关系.方法 采用聚合酶链反应-限制性片段长度多态性方法检测105个抑郁症核心家系CREB1基因上单核苷酸多态性(single nucleotide polymorphisms,SNP)rs10932201和rs6740584的等位基因与基因型分布情况.进行单位点及单倍型的传递/不平衡检验(transmission disequilibrium test,TDT).结果 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,TDT χ2 值分别为2.700(P=0.1004)和0.458(P=0.4986),差异均无统计学意义.单倍型TDT分析结果显示由rs10932201和rs6740584构成的单倍型与抑郁症存在显著性关联,差异有统计学意义(总χ2=23.458,df=3,P=0.00003241).单个单倍型A-C和A-T与抑郁症也均有显著性关联,差异有统计学意义(χ2 值分别为5.405和13.623,P值分别为0.020和0.00022).结论 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,但由这2个SNP位点构成的单倍型与抑郁症存在显著性关联,提示CREB1基因rs10932201-rs6740584单倍型可能在抑郁症的遗传学发病机制中具有重要作用.     

Association between polymorphisms in the progesterone receptor gene and endometriosis

The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormonal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 individuals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980 Australian triads (endometriosis case and two parents) and used transmission disequilibrium testing (TDT) for association with endometriosis. The five SNPs showed strong pairwise LD, and the AluIns was highly correlated with proximal SNPs rs1042839 (delta2 = 0.877, D9 = 1.00, P < 0.0001) and rs500760 (delta2 = 0.438, D9 = 0.942, P < 0.0001). TDT showed weak evidence of allelic association between endometriosis and rs500760 (P = 0.027) but not in the expected direction. We identified a common susceptibility haplotype GGGCA across the five SNPs (P = 0.0167) in the whole sample, but likelihood ratio testing of haplotype transmission and non-transmission of the AluIns and flanking SNPs showed no significant pattern. Further, analysis of our results pooled with those from two previous studies suggested that neither the T2 allele of the AluIns nor the T1/T2 genotype was associated with endometriosis.     

The relevance of Tim-3 polymorphisms and F protein to the outcomes of HCV infection

Hepatitis C virus (HCV) is one of the major causes of liver inflammation. The aim of this study was to investigate the associations of T-cell immunoglobulin and mucin domain-3 (Tim-3) polymorphisms and the alternate reading frame protein (F protein) with the outcomes of HCV infection. Three single-nucleotide polymorphisms (SNPs; rs10053538, rs12186731, and rs13170556) of Tim-3 were genotyped in this study, which included 203 healthy controls, 558 hepatitis C anti-F-positive patients, and 163 hepatitis C anti-F-negative patients. The results revealed that the rs12186731 CT and rs13170556 TC and CC genotypes were significantly less frequent in the anti-F-positive patients [odds ratio (OR)?=?0.54, 95 % confidence interval (CI)?=?0.35–0.83, p?=?0.005; OR?=?0.26, 95 % CI?=?0.18–0.39, p?<?0.001; and OR?=?0.19, 95 % CI?=?0.10–0.35, p?<?0.001, respectively), and the rs13170556 TC genotype was more frequent in the chronic HCV (CHC) patients (OR?=?1.70, 95 % CI?=?1.20–2.40, p?=?0.002). The combined analysis of the rs12186731 CT and rs13170556 TC/CC genotypes revealed a locus-dosage protective effect in the anti-F-positive patients (OR?=?0.22, 95 % CI?=?0.14–0.33, p _trend?<?0.001). Stratified analyses revealed that the frequencies of the rs12186731 (CT?+?TT) genotypes were significantly lower in the older (OR?=?0.31, 95 % CI?=?0.15–0.65, p?=?0.002) and female (OR?=?0.30, 95 % CI?=?0.17–0.52, p?<?0.001) subgroups, and rs13170556 (TC?+?CC) genotypes exhibited the same effect in all subgroups (all p?<?0.001) in the anti-F antibody generations. Moreover, the rs13170556 (TC?+?CC) genotypes were significantly more frequent in the younger (OR?=?1.86, 95 % CI?=?1.18–2.94, p?=?0.007) and female (OR?=?2.38, 95 % CI?=?1.48–3.83, p?<?0.001) subgroups of CHC patients. These findings suggest that the rs12186731 CT and rs13170556 TC/CC genotypes of Tim-3 provide potential protective effects with the F protein in the outcomes of HCV infection and that these effects are related to sex and age.